Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of transient thermotolerance by heat or other cytotoxic stressors has been reported to confer a moderate degree of drug resistance to tumor cells in vitro. In this study, a genetically stable, heat-resistant mouse B16 melanoma variant (W-H75) was tested for its sensitivity to various cytotoxic and antiproliferative agents. The heat-resistant W-H75 cells displayed a moderate two- to threefold resistance to doxorubicin, VP-16, VM-26, colchicine, cis-dichlorodiammineplatinum(II), HgCl2, and CdCl2. Marginal resistance to 4'(9-acridinylamino)methanesulfon-m-anisidide vinblastine, 1,3-bis(2-chloroethyl)-1-nitro-sourea, and NaAsO2 was observed, while no difference in sensitivity to the anticancer drugs, actinomycin D and camptothecin, was observed. Although W-H75 cells were generally more resistant than the parental cells to most of the agents that were tested, they were collaterally sensitive to the antimetabolites methotrexate and 6-mercaptopurine. Resistance of the W-H75 cells to epipodophyllotoxins and anthracyclines was not due to differences in steady-state drug accumulation. For the epipodophyllotoxin VP-16, resistance may be related to a relative decrease in the number of drug-induced DNA strand breaks in W-H75 cells. However, no difference in DNA strand breakage was observed between W-H75 and parental cells which were treated with doxorubicin, suggesting that resistance to this drug occurred by a different mechanism. The possible involvement of glutathione and glutathione S-transferase in resistance was also investigated. The glutathione content in W-H75 cells was 35% higher than that in the parental line. However, glutathione S-transferase activity appeared to be identical in both cell lines. Two other heat-resistant B16 melanoma variants, B-H103 and R-H92, were also tested for sensitivity to doxorubicin and VP-16. In contrast to the W-H75 cells, these two heat-resistant variants were hypersensitive to doxorubicin. The B-H103 cells were also hypersensitive to VP-16. This study suggests that selection for cellular resistance to heat may result in cells that have an altered sensitivity to drugs.
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PMID:Drug sensitivity of heat-resistant mouse B16 melanoma variants. 223 92

The level of expression of glutathione S-transferases (GSTs) and cytochrome P450s in breast tissue are potentially important determinants in both the susceptibility of this tissue to the mutagenic effects of chemical carcinogens and in the response of breast tumors to chemotherapy. In this study we have investigated the expression of these proteins in 41 tumor and surrounding normal breast tissue samples by measurement of substrate metabolism. Western blot analysis and immunohistochemistry. In addition, we have quantitated the concentration of alpha, mu and pi class GST subunits using radioimmunoassay. All three classes of GST were expressed in breast tissue. The pi and mu class enzymes preponderate. Both the polymorphic mu class GST as well as a further form, present in all individuals, were found in high concentration. The polymorphic mu class GST was expressed in approximately 50% of the samples, which is consistent with the frequency of this polymorphism in the population and therefore does not appear to be a factor in susceptibility to this disease. Interestingly, although levels of the alpha class GST were very low, in two tumor samples extremely high levels of the B1B1 subunit were detected. Immunohistochemical studies showed significant variability in the localization of the pi class of GST between normal epithelial cells, infiltrating plasma cells and tumor cells, and in some samples GST pi appeared to be almost absent from the tumor tissue. No direct, or inverse correlation was found between GST pi concentration determined by radioimmunoassay and estrogen receptor levels. However, when studied by immunohistochemistry estrogen receptor negative tumors did tend to have higher GST pi content. The only cytochrome P450 detectable by Western blot analysis was a member of the P450IIC gene family. This was apparently distinct from the P450IIC proteins expressed in the liver and was detected in normal and tumor tissues to a similar extent.
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PMID:Expression of glutathione S-transferases and cytochrome P450 in normal and tumor breast tissue. 226 68

Using the polymerase chain reaction (PCR), a human kidney glutathione S-transferase (GST) alpha cDNA clone (GST alpha 12 K) was synthesized; it is identical to a known liver GST alpha cDNA clone except for one base change (G----A), indicating that an alpha class gene expressed in human kidney is similar to one expressed in human liver. Comparisons were made in the expression of GST alpha and GST pi between renal cell carcinoma and adjacent non-neoplastic tissue. Messenger RNA expression in 30 cases was determined by Northern blotting, and GST protein from nine of these cases was analyzed by HPLC. The GST alpha gene products were expressed at near-zero levels. The GST pi gene product was the predominant GST in tumors, but was decreased in absolute amount compared with control tissue, the tumor/control ratios for the GST pi gene obtained by Northern blots and HPLC analysis being 0.50 +/- 0.07 and 0.36 +/- 0.07 respectively. The resulting pattern in renal cell carcinoma therefore shows a predominance of GST pi. Since it is assumed that renal cell carcinoma derives from the proximal tubular epithelial cells which are high in GST alpha, this implies a dedifferentation in the GST expression pattern.
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PMID:Decreased expression of the glutathione S-transferases alpha and pi genes in human renal cell carcinoma. 226 70

The activity of glutathione S-transferase placental form (GST-pi) was examined in 100 cases including various histologic subtypes and grading of human brain tumors and 10 cases of fetal brains by immunohistochemical studies. The 69% of cases with brain tumors were shown to be positive for GST-pi. This activity in neuroepithelial tumors tended to increase in order to tumor grading, however, medulloblastoma and primitive neuroectodermal tumor (PNET) were not immunoreactive with GST-pi. Embryonal carcinoma showed strong staining, although fetal brains were negative. The metastatic brain tumors showed the same reactivity with GST-pi as those of original carcinomas. Moreover, the difference of GST-pi activity was investigated on some brain tumors treated with or without antitumor drug, such as 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). The 85% of recurrent cases showed strong staining with GST-pi, and GST-pi activity seemed to be increased after treated with ACNU. The present study indicated that GST-pi might be a useful marker for human brain tumor, as the same conclusion was applicable to other neoplastic lesions examined previously. It is suggested that the increased GST-pi activity with malignancy of tumor may indicate the tendency to recurrence. The presence of such activity in tumor cells may also imply their acquired multidrug resistance. Our findings suggest that the evaluation of GST-pi activity in brain tumors will offer a predictive value for eventual behavior of the tumor.
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PMID:[Immunohistochemical study of placental form of glutathione S-transferase in human brain tumors and fetal brains]. 228 75

Increased levels of glutathione S-transferase (GST; RX:glutathione R-transferase; EC 2.5.1.18) mRNA, protein, and activity in tumor biopsy samples and in drug-resistant cultured cells are associated with resistance to anticancer drugs. We report that each of three full-length cloned GST cDNAs, that for pi (acidic), Ya (basic), and Yb1 (neutral), can confer drug resistance when expressed in cultured mammalian cells. In one approach, stably transfected mouse C3H/10T1/2 cells that express GST pi, Ya, or Yb1 were cloned and analyzed for drug resistance in colony-forming assays. Transiently transfected COS cells that were sorted on a fluorescence-activated cell sorter were used in the second approach to avoid interclonal variation in factors other than the recombinant GST and to show that reversion of transient GST expression correlated with loss of drug resistance. A sorting technique, developed to separate the 20% of the electroporated COS cell population that transiently expressed GST pi, Ya, or Yb1 from the nonexpressing population, was based on a GST-catalyzed intracellular conjugation of glutathione to the fluorescent labeling reagent monochlorobimane. GST Ya conferred the greatest increase in resistance to chlorambucil and melphalan (1.3- to 2.9-fold), Yb1 conferred the greatest increase in resistance to cisplatin (1.5-fold), and pi conferred the greatest increase in resistance to a racemic mixture of 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a] pyrene and 7 alpha,8 beta-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10-tetrahydrobenzo [a]pyrene and doxorubicin (1.5- and 1.3-fold) relative to controls. These resistance values to alkylating agents are commensurate with values observed clinically. Cytotoxicity curves representing recombinant GST+ populations were significantly different from their controls with P values ranging from 0.005 to 0.0001. No resistance to vinblastine was detected. Conferred drug resistance was proportional to the magnitude of GST Ya expression, and reversion of transient expression in GST Ya+ COS cell clones to a GST Ya- phenotype was associated with total loss of drug resistance.
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PMID:Expression of recombinant glutathione S-transferase pi, Ya, or Yb1 confers resistance to alkylating agents. 232 May 66

In the present study we have compared the levels of glutathione (GSH) S-transferase, GSH peroxidase and GSH reductase in human breast tumors and adjacent normal tissues obtained from the same individuals. We have also quantitated GST pi type antigen in these samples by western blotting. GST pi activity towards 1-chloro-2,4-dinitrobenzene was found to be elevated in tumors from three out of six patients (patient nos. 2, 4 and 5), whereas this activity was suppressed in tumor from patient no. 1. Results of Western blotting using antibodies raised against GST pi of human placenta were in agreement with the GST activity data. GSH peroxidase activity with cumene hydroperoxide as substrate was found to be elevated in four tumor samples (patient nos. 2, 4, 5, and 6) but suppressed in tumor from patient no. 1. On the other hand, GSH reductase activity was elevated in three samples (patients nos. 2, 4 and 5) and downregulated in the remaining three samples (patients nos. 1, 3 and 6). These results indicate that GSH-related enzymes are differentially altered in human breast tumors and GST pi type isoenzyme(s), unlike certain other human carcinomas such as colonic, are not uniformly elevated in human breast tumors.
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PMID:Differential expression of glutathione S-transferase, glutathione peroxidase and glutathione reductase in normal and malignant human breast tissues. 233 97

A wide-spectrum organ carcinogenesis model for detection of cancer modifiers in various organs was assessed in F344 male rats. After sequential treatment with diethylnitrosamine, N-methylnitrosourea, and dihydroxy-di-N-propylnitrosamine, rats were fed 500 p.p.m. sodium phenobarbital (PB: carcinogen for the liver, promoter for the thyroid) in the diet or 50 p.p.m. N,N-dibutylnitrosamine (DBN: carcinogen for the upper digestive tract, liver and urinary bladder) in the drinking water. Upon histopathological investigation at experimental weeks 18 and 24, PB was found to increase significantly the incidences of hyperplasias and adenomas of the thyroid and the numbers and areas of placental glutathione S-transferase-positive foci in the liver. DBN increased the lung tumor incidences at week 18, and brought about significant increases in both numbers and areas of lung tumors per rat at week 24. Furthermore, DBN enhanced the occurrences of hyperplasias and papillomas of the esophagus as well as hyperplasia for the forestomach at both time points. In addition, significant numbers of esophageal carcinomas and lingual papillomas developed in the group given DBN after pretreatment with the three carcinogens at week 24. Assessment of lesion yield thus clearly revealed enhancement of carcinogenesis by the test chemicals in their respective target organs, indicating the advantage of the wide-spectrum organ carcinogenesis model for detection of cancer modifiers within a limited time period in multiple organs.
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PMID:Enhancing effects of sodium phenobarbital and N,N-dibutylnitrosamine on tumor development in a rat wide-spectrum organ carcinogenesis model. 234 61

Glutathione transferase P gene becomes highly and constitutively expressed in the course of chemical hepatocarcinogenesis of the rat. To understand the mechanism of this specific gene activation and also to obtain an insight into the general mechanism of tumor marker expression, we have been studying the regulation of a cloned gene of this enzyme. Analysis of the GST-P cDNA clone revealed that this enzyme consists of 209 amino acid residues and that homologies with other isozymes, Ya and Yc, were both about 32%. The rat GST-P gene consists of seven exons and six introns. Multiple regulatory elements were found in the 5' flanking region including two TPA responsive elements (TRE), a GC box, viral enhancer, core-like elements, and a silencer. This gene was activated by a tumor promoter TPA in certain cell lines. The rat cDNA clone or a TRE binding protein, c-jun oncogene, was isolated and characterized. Analysis of the tissue distribution and expression during chemical hepatocarcinogenesis of the c-jun mRNA suggests that the GST-P gene is regulated, at least in part, by the c-jun product. Further investigation of the mechanism of expression of GST-P, particularly in terms of the interaction with c-jun products, is now underway.
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PMID:Regulation of glutathione transferase P (GST-P) gene expression during chemical hepatocarcinogenesis. 239 67

Non transformed epithelial hepatic cells (established cell line and adult rat hepatocytes) treated by liver tumor promoters, phenobarbital and biliverdin, for 24 and 48 h showed a fragmentation and loss of F-actin and a depolymerisation of microtubules. This pattern closely resembles that of transformed cells which were not susceptible to the action of promoters. In liver preneoplastic nodules obtained from rats submitted to an initiation-promotion process, actin almost completely disappeared with the concomitant appearance of a characteristic enzymatic pattern rich in GGT and GST-P. Therefore, cytoskeleton of hepatic cells is a target for tumor promoters and could play a role in promotion mechanism.
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PMID:[Modification of the cellular cytoskeleton and hepatic tumor promotion]. 240 Aug 20

A large number of human tumor cell lines of various origins have been investigated with respect to expression of glutathione-linked enzymes in the cytosol fraction. The amounts of the different enzymes were estimated by use of activity measurements and by silver staining or immunoblot analysis after electrophoresis of cytosol fractions purified by affinity chromatography on S-hexylglutathione Sepharose. Class Pi glutathione transferase was the most abundant enzyme in most tumor cells; the cell lines HepG2 and Raji were exceptions in not expressing significant amounts of this enzyme. HepG2 cells derive from hepatocytes, which normally do not express the class Pi enzyme, whereas Raji cells originate from B-lymphocytes, which normally do express a class Pi glutathione transferase. The highest level of the class Pi transferase, in terms of protein reacting with antibodies as well as enzyme activity, was noted in the colon carcinoma cell line LS174T. Hu549Pat cells, EBV-transformed B-lymphocytes, also expressed high levels of a protein reacting with antibodies specific for class Pi glutathione transferases, but did not display any significant activity with ethacrynic acid, a substrate characteristic for this class. Class Alpha and class Mu glutathione transferases, in cell lines expressing these isoenzymes, were present in significantly lower concentrations than the class Pi enzyme. Most of the tumor cells contained a class Alpha transferase composed of 27.5 kd subunits, which has the physicochemical and immunological properties of the most basic glutathione transferase found in human skin. In several cell lines, a protein was detected with an apparent subunit Mr value of 30 kd that was tentatively identified as an additional class Alpha glutathione transferase not previously described. In addition, other glutathione-linked enzyme activities, namely glutathione peroxidase, glutathione reductase and glyoxalase I, were assayed with specific substrates in the cytosolic fraction of the tumor cells; glyoxalase I could also be estimated semiquantitatively by silver staining of SDS-PAGE cells after affinity chromatography. Like the glutathione transferases, these enzymes displayed distinctly different levels of expression in the various cell lines. Thus, virtually every cell line was found to have a unique pattern of glutathione-linked enzymes, suggesting that the resistance phenotypes of the cells differ accordingly.
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PMID:Differences among human tumor cell lines in the expression of glutathione transferases and other glutathione-linked enzymes. 240 Oct 46


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